Each year, millions of women in areas of malaria transmission become pregnant and require protection from infection. Drugs currently used to prevent malaria in pregnancy are losing efficacy due to drug-resistant parasites. This Project will evaluate the safety, pharmacokinetics and efficacy of new regimens for Intermittent Preventive Treatment against pregnancy malaria (IPTp), including their long-term effects on offspring. In the studies proposed here, three new regimens (chlorproguanil-dapsone (LapDap); mefloquine; sulfadoxine-pyrimethamine (SP) + azithromycin) will be compared to the standard regimen (SP alone) for efficacy, pharmacokinetics and safety, including longterm effects on offspring. This proposed Project is based on the following hypotheses: New IPTp regimens will significantly increase birth weight and maternal hemoglobin compared to standard IPTp; New IPTp regimens will not increase the frequency of stillbirths, abortion, or fetal malformations, nor impair neurodevelopmental outcomes of offspring, compared to SP; Pharmacokinetics of antimalarial drugs in pregnant women will differ from those previously observed in nonpregnant individuals. This will be an open randomized controlled trial with four arms of IPTp. Specifically, the study will compare the clinical (maternal anemia, birth weight) and parasitological response (maternal parasitemia, placental parasitemia) to and the side effects of four IPTp regimens. The target population includes pregnant women presenting for routine antenatal care at the Morogoro Regional Hospital, where the ICDDR research center and training program will be based. The primary end-point for efficacy of the trial will be birth weight. Short-term toxicity will be assessed by careful monitoring for clinical, hematological, and biochemical abnormalities after dosing, and parasitologic response. Short and medium-term safety of IPTp will be assessed by maternal mortality, perinatal mortality, maternal complications, and clinically apparent abnormalities in the offspring. Longterm safety of IPTp regimens will be assessed in 3 year followup of offspring for hearing abnormalities or evidence of adverse neurodevelopmental consequences in standardized tests. Drug pharmacokinetics will be defined for each regimen using a Population-based approach to minimize blood sampling. The longterm objective of this Project is to identify more effective IPTp regimens to prevent malaria infection and disease in pregnant women, and to provide detailed safety and pharmacokinetics information on antimalarials for pregnant women.